Methyl mercury (MeHg) is a widespread environmental pollutant. Human exposure to MeHg has lead to catastrophic outcomes particularly when the exposure occurs in utero (e.g., Minamata Bay) . Developmental MeHg exposure leads to severe neurological abnormalities related to loss of CNS neurons and changes in cytoarchitecture. The molecular mechanism of MeHg developmental neurotoxicity is unknown. The objectives of this proposal are to study MeHg-induced changes in developmental gene expression and proliferation of CNS neuron progenitors. Preliminary studies show that exposure of developing cerebellar granule neurons to MeHg increases the expression of the POU/Homeobox gene Cns-1. Cns-1 encodes a potentially important transcriptional regulatory molecule that might control the properties of CNS neurons. Other preliminary studies suggest that MeHg inhibits proliferation of granule neuron progenitors and that Cns-1 expression occurs shortly after these progenitors exit the cell cycle and begin to differentiate. Thus, MeHg might increase Cns-1 expression indirectly by inducing granule neuron progenitors to exit the cell cycle and begin to differentiate. The proposal will test this hypothesis and evaluate the role of increased intracellular calcium as a mediator of MeHg effect on cell proliferation and Cns-1 expression. In the developing CNS, MeHg might result in a premature exit of progenitor cells from the cell cycle leading to premature differentiation. These actions of MeHg might account for some of the dysmorphogenesis associated with its developmental neurotoxicity, including a decrease in CNS cell number and a disorganization of cell within the CNS.